Cancer became the leading cause of death worldwide in 2010 and its global burden is projected to double by 2020 and to triple by 2030 (ACS data), despite enormous investments in its prevention and treatment. These efforts have led to great progress in our understanding of cancer pathogenesis. Therapeutic strategies addressing each or combinations of the cancer hallmarks and enabling features have been devised, with curative success so far limited to only a few cancers. This application proposes experiments aimed at validating a novel target for cancer therapy. Plasmalemmal vesicle associated protein-1 (PV1) is an endothelial specific protein expressed on the surface of endothelial cells of all solid tumors. Excitingly, PV1 deletion or PV1 function blockade with anti-PV1 monoclonal antibodies completely blocks the establishment or arrests the growth of tumors, respectively, in several immunocompetent mouse models of cancer (i.e. melanoma and pancreatic and bladder cancer). Mechanistically, the anti-tumor activity of anti-PV1 therapy results in a decrease of the intratumoral immune suppressive cells such as myeloid derived suppressor cells and regulatory T cells and an increase in the activated CD4 and CD8 T cells. Taken together, our data support the hypothesis that anti-PV1 therapy selectively inhibits the recruitment of immune suppressive cells, which in turn will both bolster the anti-tumor immune effector mechanisms and may also inhibit tumor angiogenesis. If correct, this will yield a completely novel multivalent strategy to inhibit tumor growth by selective inhibition of the establishment of an immunosuppressive tumor microenvironment, increase in the intratumoral T cells numbers and inhibition of angiogenesis. The location on the surface of endothelial cells and amenability to antibody blockade make PV1 an attractive therapeutic target for solid tumors, alone and especially in combination therapy. One in 52 people will be diagnosed with melanoma (lifetime risk), and while the majority is diagnosed while localized and highly treatable, eighty-five percent of those diagnosed with metastatic melanoma will not survive for five years. New treatments involving the anti-CTLA4 antibody (ipilimumab) and a novel small molecule BrafV600E inhibitor (PLX4032, vemurafenib) have recently revolutionized metastatic melanoma therapy. However, these therapies are short lived, effective in only a subset of patients or associated with significant toxicities and thus would benefit of the synergistic effects of adjuvant therapies to increase efficacy and/or manage toxicity. Using an autochthonous melanoma model system, we propose: Aim 1- to test the relevant tumor microenvironment changes underlying anti-PV1 therapy and, Aim 2- the efficacy of anti-PV1 therapy in combination with melanoma standard of care. The data we expect to obtain are relevant to the pathophysiology of cancer in general and will establish PV1 as a novel target for cancer treatment.